tbuckley/cabot-search huggingface dataset:
Effect of multimodal intervention care on cachexia in patients with advanced cancer compared to conventional management (MIRACLE): An open-label, parallel, randomized, phase 2 trial.
Authors: Bo-Hyung Kim, Chi Hoon Maeng, Jinmann Chon, Won Sub Kang, Kyounglan Kang, Mihye Woo, Il Ki Hong, Junhee Lee, Kil Yeon Lee
Journal: Journal of Clinical Oncology (2023)

e24135 Background: Cancer Cachexia (CC) is a multi-factorial process characterized by progressive weight loss, muscle mass and fat tissue wasting, and adversely affecting their quality of life and survival in patients with advanced stage of cancer. We investigated the efficacy and safety of a multi-modal intervention including anti-inflammation, omega-3-fatty acids, nutritional supplement with counselling, physical exercise, psychiatric intervention as well as Bojungikki-tang which mediates immune-modulation and reverse chronic inflammation and wasting condition as a complementary and alternative medicine compared to patients receiving best supportive care. Methods: Eligible criteria included patients with advanced stage of gastrointestinal (gastric, colorectal and pancreaticobiliary) as well as lung cancer undergoing active palliative chemotherapy. Patients are randomized into experimental arm (Multi-modal intervention care: MIC) versus control arm (Conventional Palliative Care, CPC). MIC are comprised of daily oral medications; ibuprofen 400 mg three times a day, omega-3-fatty acid 1 g twice a day, Bojungikki-tang 3.75g twice a day, oral nutritional supplement (HAMONILAN SOLN) 200 ml twice a day, and weekly physical exercise (60 minutes per visit), psychiatric assessment on every other week, and nutritional counselling total four times during the study period. CPC included basic nutritional counselling for two times provided by National Health Insurance Service, and megestrol acetate as needed (ie, anorexia≥grade 2). All interventions were provided during 12 weeks per subject. Co-primary outcomes are total lean body mass changes and handgrip strength change from the baseline. Secondary outcomes included change of fat mass and total body mass, lean body mass, and quality of life assessment (KCT0004967, NCT 04907864). Results: A total of 112 patients was planned to be assigned to the two arms (56 in each group), however, the study was terminated due to low accrual rate and the expiration of the study approval period of the national research fund, after enrolling up to 56 subjects (28 in each group). Demographic findings were even distributed between arms. The difference of median changes of total lean body mass in MIC group after 12 weeks of intervention, was numerically increased without statistical significance compared to CPC group (MIC vs CPC, 91 vs. -295 g, p= 0.3863). There was no difference of median changes of handgrip strength between MIC and CPC groups (MIC vs CPC, 0.4 vs. 0.9, p= 0.2319). Other secondary outcomes showed no differences, either. Conclusions: Multimodal intervention in this study did not show clinical meaningful improvement. We have to further investigate another method to improve cachexia. Clinical trial information: NCT04907864 .
Comparison of time of onset of leukemia with patients receiving adalimumab vs other TNF α inhibitors.
Authors: Vishal Devarkonda, Shravya Balmuri, Shiva Jashwanth Gaddam, Dinesh Keerty, Hugo Akabane
Journal: Journal of Clinical Oncology (2023)

e19034 Background: TNF α (Tumor necrosis factor alpha) inhibitors were first approved by US FDA (Food and drug administration) in the late 1990s to manage several inflammatory conditions. Theoretically, TNF α inhibitors have an elevated risk of malignancies as TNF plays a role in cell apoptosis. The development of newer human monoclonal TNF α antibodies like Adalimumab has been approved for a broader clinical spectrum of activity. However, any increase relative risk of malignancies associated with these drugs is highly debatable, with many post-marketing surveillance studies showing no significant increases in the relative risk of malignancies receiving these drugs. We hypothesize with the null hypothesis stating that there is no significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Methods: A comprehensive literature search of PubMed, Embase, and Cochrane was conducted. A total of 19 cases of acute leukemia were reported in association with TNF α inhibitors receiving it for various inflammatory conditions. Of nineteen patients, ten received Adalimumab as the last TNF α inhibitor, while nine received other TNF α inhibitors for various inflammatory etiologies. These patients received multiple lines of treatment with steroids, Thiopurines, Methotrexate, and TNF α inhibitors with varying duration of disease activity. We performed a one-way ANOVA analysis comparing the mean duration of the last TNF inhibitor with the time to diagnosis of leukemia. Results: The results indicate a significant effect [F (1, 17) = 5.652, p=0.029 &lt; 0.05]. The comparison revealed a significant difference between the patients who took Adalimumab (M=5.650; SD=3.8733) and other TNF α inhibitors (M=23.333; SD=23.2379) as the last drug. We, therefore, reject the null hypothesis as there is a significant difference in the time of onset of acute leukemia in the patients receiving Adalimumab in comparison with other TNF α inhibitors. Conclusions: In this limited study of the cases of acute leukemia reported in the literature receiving TNF inhibitors for various inflammatory conditions, patients receiving Adalimumab would have the early time of onset of leukemia in comparison with the other TNF α inhibitors. [Table: see text]
Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.
Authors: MingYuan Chen, Peiyu Huang, Xuyin Chen, Xi Ding, Guo Ling, Hao-Yuan Mo, Chongyang Duan, Li Ling, Xiong Zou, You-Ping Liu, Rui You, Yulong Xie, Jingyu Cao, Sihan Liu, Zimeng Wang, Qi Yang, Fang Qiu, Yijun Hua, Kajia Cao, Dong-Hua Luo
Journal: Journal of Clinical Oncology (2023)

6001 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .
Clonal hematopoiesis of indeterminate potential (CHIP) and association with response to bipolar androgen therapy (BAT).
Authors: Albert E Holler, Lukasz Gondek, Hua-Ling Tsai, Mark Christopher Markowski, Channing Judith Paller, Michael Anthony Carducci, Samuel R. Denmeade, Emmanuel S. Antonarakis, Jun Luo, Catherine Handy Marshall
Journal: Journal of Clinical Oncology (2023)

e17048 Background: CHIP, the expansion of hematopoietic cells carrying acquired somatic alterations associated with hematologic malignancies, is associated with increased inflammation, risk of heart disease, and poor outcomes. BAT, where testosterone levels are therapeutically manipulated between castrate levels to supraphysiologic levels, has been shown to be an effective therapy for some men with castration resistant prostate cancer. Clinical predictors of response are not established. We hypothesized that CHIP, would be negatively associated with clinical outcomes. Methods: Baseline peripheral blood from participants on the RESTORE Cohort C (NCT02090114) were analyzed for the presence of CHIP. Patients in this cohort had castration resistant prostate cancer with progressive disease after treatment with ADT alone. All participants were treated with 400mg of intramuscular testosterone cypionate every 28 days. Peripheral blood mononuclear cells were analyzed for the presence of CHIP using targeted next generation sequencing focused on 49 genes most commonly mutated in CHIP and myeloid malignancies. Given patients had metastatic and non-metastatic CRPC, progression free survival was determined based on the time to the start of the next therapy. Results: CHIP was present in 6 of 29 patients at baseline (21%) with one patient having 2 clones (Table). Median age of patients CHIP+ was 73 compared to age of 68 in the CHIP- group (p = 0.16). Median PSA was higher in the CHIP+ group (median 15, IQR 1-56) compared to the CHIP- group (median 3.5, IQR 1-57). 67% of the CHIP+ group and 57% of the CHIP- group had baseline Gleason scores of &gt; = 8. The CHIP+ group had a median PFS of 8.8 months compared to 13.3 months in the CHIP- group (HR 3.3 95%CI 1.2, 9.1; p = 0.02). This remained significant after adjusting for age. There was no difference in overall survival (HR = 2.5 95% CI 0.5,2.9; p = 0.3). Conclusions: Among men treated with BAT as first line treatment for CRPC after ADT alone, CHIP was associated with a decreased progression free survival. Larger studies are needed to understand the impact of CHIP in larger cohorts of men treated with BAT and other therapies for prostate cancer.[Table: see text]
Phase 2 trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) as first-line treatment in patients with PD-L1–positive recurrent/metastatic squamous cell carcinoma of the head and neck.
Authors: Ezra E.W. Cohen, Christophe Le Tourneau, Richard Schaub, Matthias Bartenstein, Lulu Cheng, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2023)

TPS6104 Background: Anti–PD-(L)1 therapies have improved clinical outcomes in PD-L1+ squamous cell carcinoma of the head and neck (SCCHN). However, many patients either do not respond or develop resistance, partly due to additional immune checkpoint receptors including LAG-3 and TIM-3, which are frequently coexpressed with PD-1 on tumor-infiltrating lymphocytes. In preclinical studies, LAG-3 and TIM-3 blockade showed synergistic activity with PD-1 inhibition, and triple blockade improves T-cell reinvigoration and antitumor efficacy over single/double combinations. Emerging clinical evidence also supports blockade of PD-1, LAG-3, and TIM-3 as a promising combination approach in checkpoint inhibitor–naive patients. This study aims to assess the efficacy and safety of the anti–PD-1 antibody, retifanlimab, in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) antibodies as first-line treatment in PD-L1+ recurrent or metastatic SCCHN. Methods: This randomized, double-blind, multicenter, phase 2 study (NCT05287113) includes patients with previously untreated, recurrent or metastatic, PD-L1+ (combined positive score [CPS] ≥1%) SCCHN and ECOG status of 0 or 1. Approximately 162 patients will be randomized 1:1:1 to receive (1) intravenous (IV) retifanlimab 500 mg every 4 weeks (Q4W) plus placebo controls, (2) retifanlimab plus IV INCAGN02385 350 mg Q2W plus placebo, or (3) retifanlimab plus INCAGN02385 plus IV INCAGN02390 400 mg Q2W. Patients will be stratified at randomization by LAG-3 expression (tumor proportion score ≥5% vs &lt; 5%), PD-L1 CPS (1%-19% vs ≥20%), and human papillomavirus p16 status (positive vs negative; oropharyngeal tumors only). Treatment will be administered in 4-week cycles for up to 2 years. The primary endpoint is progression-free survival (PFS; defined per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). Secondary endpoints are objective response rate per RECIST v1.1, duration of response, disease control, overall survival, and safety. Sample size calculation is based on a median PFS of 3 months, based on historical data for anti–PD-1 monotherapy in the first-line treatment setting for PD-(L)1+ advanced/metastatic SCCHN. PFS, overall survival, and duration of response data will be analyzed by the Kaplan-Meier method. Patient enrollment is ongoing. Clinical trial information: NCT05287113 .
Darolutamide for patients with androgen receptor positive salivary gland cancers (DISCOVARY): The results of phase 2 study of darolutamide monotherapy.
Authors: Susumu Okano, Makoto Tahara, Yoshinori Imamura, Hideoki Uryu, Tomoyuki Otsuka, Akira Ohkoshi, Daisuke Sano, Kiyoaki Tsukahara, Kazuchika Ono, Toyoyuki Hanazawa, Satoshi Kano, Naoki Nishio, Masato Nagaoka, Naomi Kiyota
Journal: Journal of Clinical Oncology (2023)

6093 Background: There is no standard first-line treatment for recurrent/metastatic (R/M) or unresectable locally advanced (LA) salivary gland cancer (SGC). Androgen receptor (AR) overexpression is known to be particularly high (43-92%) in SDC, depending on histology, and has been identified as a potential molecular target for SGC treatment. However, the clinical utility of this approach has not been well investigated. Here, we evaluated the efficacy and safety of darolutamide for patients with AR-positive SGC. Methods: Eligibility included LA or R/M, SGC histologically confirmed positive for AR by the central laboratory; PS 0-1; adequate organ function; and no suitable local therapy. The study consists of two sequential components: a monotherapy part with darolutamide alone (monotherapy part) and a combination part with darolutamide and goserelin (combination part). Darolutamide was given orally at 1,200 mg daily until disease progression or unacceptable toxicity. Primary endpoint for the monotherapy part was overall response rate (ORR) as determined by the investigator. Secondary endpoints were ORR by independent central review (ICR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. (ClinicalTrials.gov NCT05694819). Results: From Mar 2020 to Jan 2021, 24 patients were enrolled in the monotherapy component. Median age was 64.6 years and 23 were male. ECOG PS was 0/1 in 18/6 cases. Pathological diagnosis was salivary duct carcinoma, adenocarcinoma NOS, and carcinoma ex pleomorphic adenoma in 16, 4 and 4 patients, respectively. ORR by investigator was 8.3% (90% CI 1.5–24.0) and ORR by ICR was 20.8% (95% CI 7.1–42.2). CBR and DCR were 41.7% (95% CI 22.1–63.4) and 58.3% (95% CI 36.6–77.9), respectably. Median PFS and OS were 5.7 months (95% CI, 1.9–15.2) and not reached (95% CI, 15.5–not estimable [NE]), respectively, with a median follow-up period of 19.1 months. Nine patients (37.5%) had grade 3 or 4 treatment-related adverse events. There were no treatment-related fatal adverse events. Conclusions: This is the first prospective trial of darolutamide for AR-positive SGC. The response rate by ICR and other secondary endpoints confirmed clinically meaningful activity and a well-tolerated safety profile. Patient enrollment to the combination component is now ongoing to evaluate additional benefits. Clinical trial information: NCT05694819 .
A phase 1/2 study of STP938, a first-in-class inhibitor of CTP synthase 1, in patients with relapsed/refractory B or T cell lymphoma.
Authors: Manish R. Patel, Matthew Ahearne, Kim Linton, Christopher Fox, David John Lewis, Maureen Higgins, Brian E. Schwartz, Philip A Beer, Michael Timothy Tees
Journal: Journal of Clinical Oncology (2023)

TPS7591 Background: The rate limiting step in de novo pyrimidine synthesis is catalyzed by two homologous enzymes, CTPS1 and CTPS2. CTPS1 is essential for lymphocyte proliferation, whereas CTPS2 is sufficient in non-haemopoietic cells. STP938 is a first in class oral CTPS1 inhibitor showing &gt; 1,300-fold selectivity over CTPS2. In preclinical studies, STP938 induced death of cancer cells by apoptosis at nanomolar concentrations, and inhibited tumor growth in in vivo models of hematological malignancies. Methods: The study employs a seamless dose escalation, dose expansion design. The phase 1 dose escalation follows a standard 3+3 approach. Intra-patient dose escalation will be permitted. The recommended phase 2 dose (RP2D) will be nominated based on safety, target engagement and early signs of efficacy. An additional six patients will be treated at the RP2D with a preliminary assessment of food effect. Key phase 1 endpoints are safety and tolerability. Key phase 2 endpoints are objective response rate and duration of response. The study is open to adult patients following at least 2 prior lines of therapy who have no treatment options known to provide clinical benefit. The phase 1 study is recruiting patients with B or T cell lymphoma; the phase 2 study will be limited to cohorts of patients with specific lymphoma subtypes, which may include T cell lymphoma (peripheral or cutaneous), mantle cell lymphoma, indolent B cell lymphoma and diffuse large B cell lymphoma. Standard exclusion criteria apply; patients with ECOG performance score &gt; 2 or known CNS involvement by lymphoma are not eligible. The phase 2 study will follow a Simon two-stage design with an interim analysis for futility based on predefined, lymphoma subtype specific response rates. In the case of STP938 showing promising efficacy, provision is included in the protocol to expand a cohort using an adaptive approach based on early efficacy signals (Mehta and Pocock, 2011). Target engagement is assessed by measuring cytokine release (TNFα, IFNγ, IL2, IL8) from ex vivo stimulated patient T cells. Exploratory studies include pre- and on-treatment lymphoma biopsies to assess biomarkers of response and mechanism of action. Tumor genomics will be assessed by sequencing of circulating tumor DNA prior to treatment and at disease progression using a bespoke genomic assay designed to elucidate biomarkers of response and understand mechanisms of resistance. The phase 1 study (NCT05463263) opened to enrolment in the US and UK in September 2022. No dose limiting toxicities were observed in the first cohort of 3 patients. The phase 2 study will include additional centers in France. Clinical trial information: NCT05463263 .
CAR-T cells targeting CD38 and LMP1 and anti-tumor activity against NK/T cell lymphoma.
Authors: Hongwen Li, Zhuangzhuang Shi, Yuyang Gao, Zhaoming Li, Mingzhi Zhang
Journal: Journal of Clinical Oncology (2023)

e19529 Background: Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma with poor prognosis. In the past decade, chimeric antigen receptor transduced T (CAR-T) cell therapy has been a promising strategy against hematologic malignancies. Researchers have evaluated the efficacy of CAR-T cell targeting CD38 in multiple myeloma and NKTCL. LMP1 may induce a malignant transformation in B cells and epithelial cells, making it a non-negligible molecule in NKTCL. These suggest the potential clinical administration of CD38 and LMP1 targeting therapy. Methods: Four second-generation CAR-T cells including two single-targeted CAR (CD38-CAR and LMP1-CAR) and two tandem CAR (CD38-LMP1 Tan CAR 1 and Tan CAR 2) were constructed. Then the effects of four CAR-T cells on NKTCL cells were evaluated both in vitro and in vivo. Results: Four CAR-T cells could effectively eliminate malignant target-positive NKTCL cells in vitro. They could be activated and produce inflammatory cytokines in a target-dependent manner. Stimulated by CD38+LMP1+ NKTCL cells, two Tan CAR-T cells produced more IL-13, Granzyme B, IFN-γ and TNF-α than LMP1-CAR-T cells. In vivo test showed that CAR-T cells also exhibit significant anti-tumor effects in a xenotransplant NKTCL mice models. Two Tan CAR-T cells showed higher cytolytic activity against CD38+LMP1+ NKTCL cells than single-targeted CAR-T cells both in vitro and in vivo. Conclusions: We explored the feasibility of CAR-T cell therapy targeting both CD38 and LMP1 molecule. Our results indicated a promising effective therapeutic strategy for NKTCL.
Clinical characterization of responders to first line (chemo)immunotherapy in platinum-sensitive recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC).
Authors: Silvia Buriolla, Stefano Cavalieri, Andrea Franza, Simone Rota, Cristiana Bergamini, Salvatore Alfieri, Imperia Nuzzolese, Elena Colombo, Arianna Ottini, Lisa F. Licitra, Carlo Resteghini
Journal: Journal of Clinical Oncology (2023)

e18017 Background: RM HNSCC patients (pts) with combined positive score (CPS) ≥1 benefit from immunotherapy (IO), either alone or with chemotherapy (CIO). No survival outcome indicators are available. We aim to characterize a real world cohort of RM HNSCC pts treated at a tertiary cancer center. Methods: We analyzed 37 consecutive RM HNSCC pts treated with IO or CIO from 2016 to 2022. We divided pts in responders (R) and non responders (NR) if they achieved an objective response or disease stability/progression as best response. For group comparisons, we considered the following clinical variables: age, gender, smoking status, primary HNSCC site, HPV status, ECOG performance status, disease sites at RM diagnosis (local, regional, distant), time to RM diagnosis (TTR). For categorical variables, we compared the clinical characteristics of the 2 groups using the chi squared or Fisher’s exact tests, as appropriate. For age we used the Mann-Whitney test. For TTR we used the Cox proportional hazard model. Outcomes (progression free and overall survival, PFS and OS, respectively) were assessed with Kaplan Meier method and compared with log-rank test. Statistical significance was set at 0.05. Results: Clinical characteristics are reported in the table. Objective response rate (ORR) was 32%, median DoR 7.5 months (95% confidence interval, CI 2.07-not reached). None of the examined clinical variables were significantly different in the groups (R vs NR in the overall population, in IO- and CIO-treated pts). The only major difference between cohorts was survival, which was significantly longer in R vs non-R (Table). Conclusions: With the limits of a retrospective analysis, we observed a longer survival in R compared to NR. None of the main clinical characteristics were predictive of objective response to (C)IO. Further studies are needed to define predictive factors of response, and to enhance the ORR in first-line IO-based treatments. [Table: see text]